Carbazolone derivatives

ABSTRACT

The invention relates to carbazolone derivatives of the formula ##STR1## wherein A stands for a group of formula 
     
         --CH.sub.2 --R                                             (V), 
    
      wherein R means a hydroxyl or 2-methyl-1H-imidazol-1-yl group; 
     B represents a group of formula ##STR2##  wherein R 1  means hydrogen or a methyl or ethyl group; or A and B together form a group of formula ##STR3##  wherein R 2  means a methyl or ethyl group; or A and B together form a group of formula ##STR4## The above compounds are useful intermediates in the synthesis of ondansetron of formula ##STR5## chemically 9-methyl-3-[(2-methyl)-1H-imidzol-1-yl)methyl]1,2,3,9-tetrahydro-4H-carbazol-4-one. 
     The invention further relates to a novel process for the preparation of compounds of the formula (I), wherein A and B are the same as in formula (I) but B may be also hydrogen. Thus, this novel process is suitable for the preparation of ondansetron itself.

The invention relates to novel carbazolone derivatives of formula##STR6## wherein A stands for a group of formula

    --CH.sub.2 --R                                             (V),

wherein R means a hydroxyl or 2-methyl-1H-imidazol-1-yl group;

B represents a group of formula ##STR7## wherein R₁ means hydrogen or amethyl or ethyl group; or A and B together form a group of formula##STR8## wherein R₂ means a methyl or ethyl group; or A and B togetherform a group of formula ##STR9##

Furthermore, the invention relates to a process for the preparation ofthe above compounds.

The compounds of formula (I) are valuable intermediates in the synthesisof9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-oneof formula ##STR10## (generic name: ondansetron) and its acid additionsalts, preferably the hydrochloride dihydrate.

Thus, the invention relates also to a novel process for the preparationof ondansetron of the formula (II).

Due to its selective 5-HT₃ antagonistic effect, ondansetron is anexcellent antiemetic drug, inhibiting vomiting and nausea by decreasingthe gastric motility, mainly during cancer chemotherapy (see GB patentspecification No. 2,153,821).

Several processes have been published for the preparation ofondansetron.

According to a process described in the published European patentapplication No. 219,929, the imidazolyl-alkyl side chain is introducedby a three-step synthesis onto the methylene group neighbouring the oxogroup of the 1,3-cyclohexanedione monoenol ether used as startingsubstance. After that the enol ether group is replaced by a2-methyl-2-phenylhydrazino group and the phenylhydrazone obtained issubjected to a Fischer's indole synthesis. The drawbacks of thisprocess, comprising five steps, reside in the use of dangerous andexpensive reagents (butyl lithium, dimethylmethyleneammonium iodide,1-methyl-1-phenylhydrazine) and technological steps, which result amoderate yield and which are difficult to carry out, in some cases, andto increase to industrial scales (c.f. column chromatography,temperature of -70° C.). The overall yield of ondansetron is only 9.57%,calculated for 1,3-cyclohexanedione monoenol ether.

According to another method described in the published European patentapplication No. 221,629, after reacting animidazolylalkyl-1,3-cyclohexanedione monoenol ether with 2-iodoaniline,the enamine obtained is cyclized with palladium(II) acetate. Theindole-N atom of the product thus formed is methylated in the last step.The drawbacks of this process are the same as those of the former one.The overall yield of ondansetron is at most 1.0%, calculated for1,3-cyclohexanedione monoenol ether used as starting substance.

According to the above-said GB patent specification No. 2,153,821 (whichis equivalent to the Hungarian patent specification No. 193,592),3-(dimethylaminomethyl)-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one isused as starting substance, which is heated with 2-methylimidazole toobtain ondansetron. However, the starting tertiary amine is similarlybasic in character as ondansetron, which causes separation difficultiesin the purification of the final product.

Another important disadvantage of this process consists therein that noteaching for the preparation and characterization of the startingtertiary amine compound can be found either in the specification itselfor in the literature.

Peculiarly, the above-said patent specification indicates this tertiaryamine to be known per se and, in addition, ondansetron can be preparedtherefrom in an other way, too. After quaternizing the tertiary aminewith methyl iodide, trimethylamine is split off from the obtainedmethoiodide by Hofmann's elimination reaction to give9-methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one. Thethus-obtained electrophilic conjugated enone is subjected to an additionreaction with 2-methylimidazole (see Example 8 of the specification).The surprisingly moderate yield of 43.2% of the reaction shows that thesignificance of this simple direct addition, starting from the separatedenone, should not be overestimated.

However, the reaction of 2-methylimidazole with the said tertiary aminecompound (c.f. Example 7) results in a good yield of ondansetron (100%of crude product, 82% of recrystallized product). These data suggestthat the reaction mechanism of the last step in the known synthesis ofondansetron is decisively not an elimination-addition reaction in itscharacter but has another type, i.e. N,N'-transamination by directsubstitution.

The present invention is aimed at developing a preparation process, inthe course of which a pure final product can be obtained from novelintermediates through selective reactions, being easy to carry out andincrease to an industrial scale, whereby the above drawbacks can beeliminated.

The invention is based on the surprising discovery that any of the newalkoxalylated 4-carbazolones of formula ##STR11## wherein R₁ means amethyl or ethyl group, or formula ##STR12## can N-monoalkylate2-methylimidazole of formula ##STR13## and the obtained intermediate offormula ##STR14## chemically9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylicacid, can be converted into ondansetron of the formula (II) bydealkoxalylating with a nucleophilic reagent.

The surprising character of this solution can be explained as follows:

It is well-known that the N-acylation of imidazoles can easily becarried out in a non-aqueous medium by using strong acylating agents,e.g. reactive esters (Alan E. Katritzky, Charles W. Rees: "ComprehensiveHeterocyclic Chemistry", Vol 5 p 390-393) Based on this one could expectthat the substituted glioxylic acid esters of the formula (Ib) or thelactone of the formula (Ic), both being strong acylating agents, wouldacylate 2-methylimidazole of the formula (IV) to give the followingcompound: ##STR15##

In an entirely surprising manner the methylene part of theC-hydroxymethyl group was attached to the nitrogen atom of2-methylimidazole in an N-alkylation reaction, giving the compound ofthe formula (Id), being sterically more dense, rather than theN-acylimidazole of the formula ("IX").

Thus, the present invention relates to novel compounds of formula##STR16## wherein A stands for a group of formula

wherein R means a hydroxyl or 2-methyl-1H-imidazol-1-yl group;

B represents a group of formula ##STR17## wherein R₁ means hydrogen or amethyl or ethyl group; or A and B together form a group of formula##STR18## wherein R₂ means a methyl or ethyl group; or A and B togetherform a group of formula ##STR19##

The new compounds are as follows:

3-ethoxalyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one,

methyl 3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylate,

ethyl3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylate

3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylicacid lactone and

9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylicacid.

Further, the invention relates also to a process for the preparation ofthe partially novel, partially known compounds of formula ##STR20##wherein A stands for a group of formula

    --CH.sub.2 --R                                             (V),

wherein R means a hydroxyl or 2-methyl-1H-imidazol-1-yl group;

B represents hydrogen or a group of formula ##STR21## wherein R₁ meanshydrogen or a methyl or ethyl group; or A and B together form a group offormula ##STR22## wherein R₂ means a methyl or ethyl group; or A and Btogether form a group of formula ##STR23## which comprises a) reactingthe ketone of formula ##STR24## with a di(C₁₋₂ alkyl)oxalate in thepresence of a basic agent in order to obtain a novel compound of theformula ##STR25## wherein R₂ stands for a methyl or ethyl group; b)reacting a compound of the formula (Ia), wherein R₂ is as defined instep a) above:, with formaldehyde in the presence of a basic catalyst ina non-acidic protic solvent in order to obtain a novel compound of theformula (Ib), wherein R₁ is a methyl or ethyl group; or reacting acompound of the formula (Ia), wherein R₂ is as defined in step a) abovewith formaldehyde in the presence of a basic catalyst in an aproticsolvent in order to obtain the novel compound of the formula (Ic);

c) reacting a compound of the formula (Ib), wherein R₁ is as defined instep b) above, or the compound of the formula (Ic) with2-methylimidazole of the formula (IV) in order to obtain the novelcompound of the formula (Id);

d) reacting the compound of the formula (Id) with a base, preferably analkali metal carbonate or hydroxide, in order to obtain ondansetron ofthe formula (II),

and, if desired, converting ondansetron of the formula (II) into itspharmaceutically acceptable acid addition salt.

According to variant b) of the above process, the compounds of formula(Ia), wherein R₂ is as defined above, are reacted with 1 to 2 moles,preferably 1.2 to 1.6 moles, of formaldehyde in the presence of not morethan 0.2 mole of a basic catalyst, preferably an alkaline metalcarbonate or a trialkyl amine. The reaction is carried out preferably inmethanol or ethanol if a compound of the formula (Ib) is to be prepared.If the compound of the formula (Ic) is to be prepared, the reaction withformaldehyde is carried out preferably in a dipolar aprotic solvent likeacetonitrile or acetone. When in variant c) of the process of theinvention a compound of the formula (Ib), wherein R₁ means a methyl oran ethyl group, or the compound of the formula (Ic) is used as startingsubstance, the oxalyl group is removed by alcoholysis of the C--C bondin the presence of a C₁₋₄ alkanol and the group cleaved off is bound bysalt formation with a base being stronger than 2-methylimidazole,preferably with triethylamine.

2-Methylimidazole is used in an amount of 1.0 to 3.0 moles, preferably1.5 to 2.0 moles, calculated for a compound of the formula (Ib), whereinR₁ means a methyl or ethyl group, or for the compound of the formula(Ic).

When carrying out variant c) of the process of the invention, a compoundof the formula (Ib) or (Ic) is heated with 2-methylimidazole in anaprotic solvent until the reaction becomes complete. Then in variant d)the oxalyl group is removed by a nucleophilic agent to obtain the targetcompound of the formula (II).

According to a preferred embodiment of variant c) of the process of theinvention, 1.0 to 3.0 moles, preferably 1.5 to 2.0 moles of2-methylimidazole, 1.0 to 2.0 moles of ethanol and a base stronger than2-methylimidazole, advantageously 1.1 to 1.5 moles of triethylamine,each calculated for 1 mole of a compound of the formula (Ib) or (Ic),are used in an ether-type solvent such as dioxane, or in a dipolaraprotic solvent, preferably dimethylformamide, dimethylsulfoxide orsulfolane. The reaction requiring heating is carried out at atemperature between 70° C. and 200° C., preferably between 100° C. and150° C., for 0.25 to 20 hours, advantageously 0.25 to 5 hours, then theproduct of the formula (II) is precipitated by dilution with water or bysalt formation and isolated by filtration.

The compound of the formula (II) is obtained from the compound of theformula (Id) by using an aqueous alkaline metal hydroxide or alkalinemetal carbonate solution at a temperature from 20° C. to 100° C.preferably a potassium hydroxide or carbonate solution at 30° to 70° C.The compound of the formula (II) obtained in the free base form may beconverted into its monohydrochloride dihydrate in a way known per se.

In comparison to the processes known in the art the advantages of theprocess according to the invention are as follows.

a) The process consists of reactions easy to carry out and to increaseup to industrial scales.

b) The alkoxalyl group proves to be an excellent adjuvant function forthe selective introduction of the imidazolylmethyl side chain, which islater easily split off in the form of an oxalate salt, in some casesspontaneously, in situ in the reaction mixture.

c) The reactions can be performed in very good yields of 70 to 90% toresult in well-isolable and well-characterizable crystalline substancesin all cases.

d) An additional advantage appears also therein that the intermediatesof the reaction sequence do not contain any basic group; therefore, thefinal product is easy to purify.

Thus, the isolation of a pure final product becomes extremely simplesince none of the possible or actual impurities contains a basic group.In contrast, the synthesis disclosed in the above-cited GB patentspecification No. 2,153,821 proceeds through the intermediate3-(dimethylaminomethyl)-carbazol-4-one, i.e. through a substance basicin its character and difficult to remove.

The invention is illustrated in detail by the following Examples.

EXAMPLES 1 Preparation of3-ethoxalyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one [compound offormula (Ia), wherein R₂ means an ethyl group]

3.0 g (0.13 mole) of sodium metal are portionwise added to a stirredmixture containing 19.93 g (0.1 mole) of9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one of formula (III), 19.0 g(0.13 mole) of diethyl oxalate, 2 g of ethanol and 200 ml of dioxane.The slightly warming reaction mixture is stirred at 40° to 50° C. for 4hours, then 16 g of glacial acetic acid and finally 200 ml of water areadded thereto at room temperature. After filtering off the yellowcrystalline suspension, the precipitate is washed with water and driedto give the title compound in a yield of 24 g (80.2%), m.p.: 118°-120°C.

The active ingredient content of the product amounts to 98.4% based onpotentiometric titration with sodium hydroxide solution.

    ______________________________________                                        IR spectrum (KBr), γ.sub.max :                                          ______________________________________                                        OH              3600-2000 cm.sup.-1                                           C═O (ester) 1727 cm.sup.-1                                                O═C--C═C                                                                              1590 cm.sup.-1                                                                1578 cm.sup.-1                                                C--O--C (ester) 1213 cm.sup.-1                                                ═C--OH (enol)                                                                             1185 cm.sup.-1                                                Ar--H (bending)  754 cm.sup.-1                                                ______________________________________                                    

    ______________________________________                                        .sup.1 H--NMR (DMSO-d6) δ ppm:                                          ______________________________________                                         ##STR26##           1.47 (3H, t)                                             --CH.sub.2 --        2.75 (2H, t)                                             --CH.sub.2 --        3.12 (2H, t)                                             CH.sub.3 --N         3.60 (3H, s)                                              ##STR27##           4.36 (2H, q)                                             Ar--H                7.24 (2H, m)                                                                  8.00 (1H, dd)                                                                 8.13 (1H, dd)                                            ______________________________________                                    

EXAMPLE 2 Preparation of3-ethoxalyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one [compound offormula (Ia), wherein R₂ means an ethyl group]

After adding 7.1 g (0.13 mole) of solid sodium methoxide to a stirredmixture containing 19.93 g of the ketone of formula (III) (for thechemical name see Example 1), 19 g of diethyl oxalate and 200 ml of1,2-dimethoxyethane, the process described in Example 1 is followed toobtain 23.1 g (77.2%) of the title compound, m.p.: 117°-120° C.

The titrimetrically determined active agent content of the product is97.9%.

The spectroscopical data of the product are the same as described inExample 1.

EXAMPLE 3 Preparation of methyl3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylate

After dropwise adding 0.2 g of triethylamine to a stirred suspension of3.00 g (0.01 mole) of the ethoxalyl compound of formula (Ia), wherein R₂is an ethyl group (chemically3-ethoxalyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one), and 0.45 gof paraformadehyde in 20 ml of methanol, the reaction mixture is heatedat 55° to 60° C. for 1 hour. After cooling the reaction mixture isfiltered off, the precipitate is washed with methanol and dried to give2.45 g (78.7%) of the title compound, m.p.: 238-242° C. (withdecomposition).

    ______________________________________                                        IR spectrum (KBr), γ.sub.max :                                          ______________________________________                                        O--H            3350 cm.sup.-1 (broad)                                        C═O         1782 cm.sup.-1 (alpha-oxo + ester)                                            1628 cm.sup.-1 (alpha-oxo + ester)                            C--O--C         1137 cm.sup.-1 (ester)                                        C--OH           1056 cm.sup.-1                                                Ar--H (bending)  744 cm.sup.-1                                                ______________________________________                                    

    ______________________________________                                        .sup.1 H--NMR (DMSO-d6) δ ppm:                                          ______________________________________                                        --CH.sub.2 --         2.1 (1H, m)                                                                  2.55 (1H, m)                                             --CH.sub.2 --        2.98 (1H, m)                                                                  3.20 (1H, m)                                             CH.sub.3 --O--       3.25 (3H, s)                                             CH.sub.3 --N         3.68 (3H, s)                                             --C--CH.sub.2 OH     3.99 (1H, d)                                                                  4.50 (1H, d)                                             Ar--H                7.21 (2H, m)                                                                  7.47 (1H, dd)                                                                 8.00 (1H, dd)                                            ______________________________________                                    

EXAMPLE 4 Preparation of ethyl3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylate

The process described in Example 3 is followed, except that ethanol isused instead of methanol. In this way 2.65 g (80.55%) of title compoundare obtained, m.p.: 240°-245° C. (with decomposition).

IR spectrum: the characteristic bands are identical with those of themethyl ester.

    ______________________________________                                        .sup.1 H--NMR (DMSO-d6) δ ppm:                                          ______________________________________                                         ##STR28##           1.15 (3H, t)                                             --CH.sub.2 --        2.05 (1H, m)                                                                  2.58 (1H, m)                                             CH.sub.2 --          2.97 (1H, m)                                                                  3.18 (1H, m)                                              ##STR29##           3.45 (2H, q)                                             CH.sub.3 --N         3.68 (3H, s)                                             --C--CH.sub.2 OH     3.94 (1H, d)                                                                  4.48 (1H, d)                                             Ar--H                7.21 (2H, m)                                                                  7.47 (1H, dd)                                                                 8.00 (1H, dd)                                            ______________________________________                                    

EXAMPLE 5 Preparation of3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylicacid lactone [compound of formula (Ic)]

After adding 0.1 g of triethylamine to a stirred suspension containing3.00 g (0.01 mole) of the ethoxalyl compound of the formula (Ia),wherein R₂ means an ethyl group (for the chemical name see Example 3) in20 ml of acetone, 1.13 g (0.015 mole) of formol solution are dropwiseadded to the mixture. The suspension becomes clear within 1 to 2 minutesand crystals begin to precipitate. After further stirring at 35° to 40°C. for one hour, the reaction mixture is cooled down to roomtemperature, filtered off, the precipitate is washed with 50% acetoneand dried to give 2.10 g (74.2%) of the title compound, m.p.: 242°-244°C.

    ______________________________________                                        IR spectrum (KBr), γ.sub.max :                                          ______________________________________                                        O--H               1794 cm.sup.-1 (lactone)                                   C═O            1782 cm.sup.-1 (alpha-oxo)                                 C═O            1642 cm.sup.-1 (carbazol-4-one)                            C--O--C            1259 cm.sup.-1                                             Ar (skeleton vibration)                                                                          1579 cm.sup.-1                                             Ar--H (bending)     755 cm.sup.-1                                             ______________________________________                                    

    ______________________________________                                        .sup.1 H--NMR (DMSO-d6) δ ppm:                                          ______________________________________                                        --CH.sub.2 --        2.4 (1H, m)                                                                  1.75 (1H, m)                                              --CH.sub.2 --       3.09 (1H, m)                                                                  3.78 (1H, m)                                              CH.sub.3 --N--      3.75 (3H, s)                                              --C--CH.sub.2 O     4.53 (1H, d)                                                                  5.04 (1H, d)                                              Ar--H               7.22 (2H, m)                                                                  7.53 (1H, dd)                                                                 7.92 (1H, dd)                                             ______________________________________                                    

EXAMPLE 6 Preparation of3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylicacid lactone [compound of formula (Ic)]

To a suspension containing 29.93 g (0.10 mole) of3-ethoxalyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one and 10.5 g(0.14 mole) of formol solution in 200 ml of acetonitrile, 1.0 g (0.0072mole) of potassium carbonate is added. The reaction mixture is stirredat 30° to 35° C. for one hour. Subsequently, the process described inExample 5 is followed to obtain 22.46 g (75.04%) of the title compound,m.p.: 240°-243° C.

The spectroscopic data of the product are identical with those of theproduct of Example 5.

EXAMPLE 7 Preparation of ethyl3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-glyoxylate

To a mixture containing 0.85 g (0.003 mole) of3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylicacid lactone of the formula (Ic) and 18.0 of ethanol, 0.2 g ofconcentrated sulfuric acid is dropwise added under stirring. Thereaction mixture is boiled under reflux for 3 hours, then cooled downand filtered off. The precipitate is washed with ethanol and dried togive 0.35 g (35.43%) of the title compound, m.p.: 241°-245° C. (withdecomposition).

The spectroscopic data of the product are identical with those of theproduct of Example 4.

EXAMPLE 8 Preparation of ondansetron base (chemically9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one)

A mixture containing 2.83 g (0.01 mole) of3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3glyoxylicacid lactone of the formula (Ic), 15 ml of dioxane, 1.32 g oftriethylamine, 1.0 g of ethanol and 1.64 g (0.02 mole) of2-methylimidazole is boiled under reflux while stirring for 5 hours.Thereafter, the reaction mixture is diluted with 45 ml of water andcooled down. The precipitate is filtered off, washed with aqueousdioxane and dried to obtain 2.56 g (87.3%) of the title compound, m.p.:220°-223° C.

    ______________________________________                                        IR spectrum (KBr), γ.sub.max :                                          ______________________________________                                        C═O               1623 cm.sup.-1                                          Ar (skeleton)         1579 cm.sup.-1                                          N--CH.sub.3           1483 cm.sup.-1                                                                1460 cm.sup.-1                                          HetAr--H (bending)     781 cm.sup.-1                                          Ar--H (bending)        758 cm.sup.-1                                          ______________________________________                                    

    ______________________________________                                        .sup.1 H--NMR (DMSO-d6) δ ppm:                                          ______________________________________                                        --CH.sub.2 --     1.98 (1H, a, axial)                                                           2.17 (1H, e, equatorial)                                    CH.sub.3 --C      2.67 (3H, s)                                                --CH.sub.2 --     2.94 (1H, a)                                                                  3.11 (1H, e)                                                --CH--            3.10 (1H, m)                                                CH.sub.3 --N      3.68 (3H, s)                                                --CH--CH.sub.2 --N                                                                              4.30 (1H, dd)                                                                 4.68 (1H, dd)                                               Ar--H             7.25 (2H, m)                                                                  7.50 (1H, dd)                                                                 8.03 (1H, dd)                                               HetAr--H          7.57 (1H, d)                                                                  7.67 (1H, d)                                                ______________________________________                                    

EXAMPLE 9 Preparation of ondansetron base

A mixture containing 3.29 g (0.01 mole) of ethyl3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylateof the formula (Ib), 10 ml of dimethylsulfoxide, 1.32 g oftriethylamine, 0.5 g of ethanol and 1.64 g (0.02 mole) of2-methylimidazole is stirred at 110° to 120° C. for 3 hours. Afterdiluting the reaction mixture with 40 ml of water, cooling down andfiltering off, the precipitate is washed with water and dried to obtain2.20 g (75%) of the title product, m.p.: 219°-223° C.

The spectroscopic data of the product are in agreement with those of theproduct of Example 8.

EXAMPLE 10 Preparation of ondansetron base

a) Preparation of9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-one-glyoxylicacid [compound of formula (Id)]

A mixture containing 2.83 g (0.01 mole) of3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylicacid lactone [compound of the formula (Ic)] and 1.64 g (0.02 mole) of2-methylimidazole in 6.0 ml of sulfolane (tetramethylenesulfone) isheated in an oil bath of 150 to 160° C. for 15 minutes while stirring.After cooling down and diluting with 60 ml of acetone the precipitate isfiltered off, washed with acetone and dried to give 0.95 g of the titlecompound, m.p.: 190°-200° C. (with decomposition). The active agentcontent of this product measured by titration with perchloric acid inglacial acetic acid was found to be 96%. In the combined filtrate of thereaction, ondansetron could be detected by thin layer chromatography.The most important characteristics of the title product are as follows:

    ______________________________________                                        IR spectrum (KBr), γ.sub.max :                                          ______________________________________                                        X--H        3440 cm.sup.-1                                                                2650 cm.sup.-1                                                                2550 cm.sup.-1                                                                1973 cm.sup.-1                                                    C═O     1628 cm.sup.-1 (alpha-oxo + carbazol-4-one)                       --COO--     1595 cm.sup.-1                                                    Ar--H (bending)                                                                            763 cm.sup.-1                                                    ______________________________________                                    

b) Preparation of ondansetron base

A suspension containing 0.73 g (0.002 mole) of the product of theformula (Id) prepared in the preceding step a) and 0.40 g (0.0061 mole)of 85% potassium hydroxide in 20 ml of water is stirred at 45° to 50° C.for one hour. After cooling down and filtering off the suspension, theprecipitate is thoroughly washed with water and dried to give 0.50 g(85.32%) of the title product, m.p.: 223°-225° C.

The spectroscopic data of the product are in agreement with those of theproduct of Example 8.

The active agent content of the product was found to be 97.6% based onthe potentiometric titration with hydrochloric acid.

EXAMPLE 11 Preparation of9-methyl-3-[(2-methyl-1H-imidazol-1-yl)-methyl]-1,2,3,9-tetrahydro-4H-carbazol-4-onehydrochloride dihydrate

The process described in Example 8 is followed, except that aftercooling down the reaction mixture to room temperature after boiling, 20ml of 37% aqueous hydrochloric acid are added thereto. Then, theprecipitate is filtered off, washed with isopropanol and dried to obtain2.40 g (65.6%) of the title salt, m.p.: 178°-180° C.

The active agent content of the product was found to be 100.3% based onpotentiometric titration with sodium hydroxide solution.

The theoretical water content is 9.85% (calculated for C₁₈ H₁₉ N₃O.HCl.2H₂ O). The water content measured is 10.03%.

What we claim is:
 1. Novel compounds of the formula ##STR30## wherein Astands for a group of formula

    --CH.sub.2 --R                                             (V),

wherein R means a hydroxyl group; B represents a group of formula##STR31## wherein R₁ means hydrogen or a methyl or ethyl group; A and Btogether form a group of formula ##STR32##
 2. A compound selected fromthe group consisting ofmethyl3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylateethyl3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylateand3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylicacid lactone.
 3. The compound of claim 2 which is3-hydroxy-methyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylicacid lactone.